nutritional strategies for cognitive decline

Nutritional strategies for cognitive decline

Nina Bailey BSc MSc, PhD RNutr

1

Defining dementia

• Dementia is an umbrella term, used to describe a syndrome that can have many different causes and that is characterised by gradual decline in cognitive abilities and neuropsychiatric symptoms

• The most common dementia types include Alzheimer’s disease, vascular dementia, fronto-temporal dementia, Lewy body dementia, Korsakoff's syndrome, Huntingdon’s chorea and Parkinson's disease

• Processes related to cognitive decline/dementia begin to damage the brain many years, if not decades, before symptoms become apparent and cause a progressive decline in functioning as more of the brain is damaged, making early intervention key to slowing/preventing cognitive decline

Understanding the mechanisms and those dietary factors that influence cognitive health may provide insight into an optimum time window when dietary interventions would be most beneficial for changing the course of the disease

Well established risk factors for cognitive decline

Risk factor Modifiable?Age XGenetics (i.e., APO4) XOverweight/obese Hypertension High cholesterol Dyslipidaemia Type II diabetes Poor mental or social stimulation Poor education status Low activity/sedentary lifestyle Smoking

Additional nutrient & lifestyle factors

Risk factor Modifiable?High HbA1c (with or without diabetes) Poor adherence to Mediterranean diet Low omega-3 intake/ fish consumption Low intake of B vitamins Low vitamin D exposure/ intake/ status Low antioxidant intake High oxidative stress High alcohol consumption Low intake of polyphenols High stress/ cortisol/ HPA axis activity Poor sleep quality/ sleep deprivation

‘New’ environmental stressors Reactive Hypoglyceamia Immune System Activation

High calorie diet

Muscle/fat ratio

Bosma-den Boer, M. M., M. L. van Wetten, et al. (2012). "Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering." Nutr Metab (Lond) 9(1): 32.

Free radicals, reactive oxygen species (ROS) & oxidative stress

Many neurodegenerative diseases are characterised by aggregates and inclusions of aberrant proteins Degradative pathways such as the ubiquitin proteasome system, are responsible for the clearance of toxic protein aggregates

ROS can modify proteins,leading to protein unfolding and aggregation

Alzheimer's disease

Parkinson's disease

Huntingdon’s disease

Frontotemporal lobar degeneration

Amyloid- -synuclein Ataxins Tau

Abnormal misfolding and aggregation

Neurodegeneration

ROS

Aging

APO4

Inflammation

Neuronal dysfunction Neuronal death

Proteasome inhibition(degrades unneeded or damaged proteins)

Homocysteine

Pollution

Stress

Injury/trauma/infection

Metabolism

Li J, O W, Li W, Jiang ZG, Ghanbari HA. Oxidative stress and neurodegenerative disorders. Int J Mol Sci. 2013 Dec 16;14(12):24438-75.

Neurotrophins play a role in the maintenance, repair and genesis of neurons including serotonergic and noradrenergic neurones

Brain-Derived Neurotrophic Factor (BDNF) is involved in neuronal survival and synaptic plasticity, and considered to be an important biomarker for cognitive decline as well as for psychiatric conditions such as depression and bipolar disorder

Activation of tryptophan 2,3-dioxygenase (TDO), present in liver and brain, is up regulated by cortisol whilst cytokines (such as IL-1. IL-6 and TNF-) activate IDO and kynurenine monooxygenase (KMO)

Not only are serotonin levels reduced as a result of the diversion of tryptophan but elevated quinolinic acid production has neurotoxic effects via agonist actions on N-methyl-D-aspartate receptors (NMDA) triggering neuronal apoptosis

Elevated quinolinic acid accumulation in certain areas of the brain tissue is linked to cognitive issues

Oxenkrug, G. F. (2010). "Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later." Isr J Psychiatry Relat Sci 47(1): 56-63.

The kynurenine (KYN)/tryptophan ratio and cognitive function

The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is a main tryptophan metabolic pathway and shares tryptophan with the serotonin (5-HT) pathway

Elevated homocysteine (poor recycling)

Elevated homocysteine levels damage cells directly by promoting oxidative stress

Reduced glutathione production results in compromised detoxification

Reduced methyl donor production

The methylation cycle supplies methyl groups for a large number of methylation-dependent reactions, including those involved in the synthesis of substances including creatine, choline, carnitine, coenzyme Q10, melatonin and myelin proteins

Low SAMe levels also result in a reduction in neurotransmitter production

Methylation is a fundamental process required for normal cell division and DNA repair

Compromised methylation is also implicated in accelerated ageing!!

Role and benefits of a healthy methylation cycle Neurotransmitter production:

o Mood o Memory o Learning o Gut function

Antioxidant activity: o Increased glutathione production o Reduced free radical production

Cardioprotection: o Reduced risk of cardiovascular disease and

stroke

Detoxification: o Improved liver function o Increased energy o Improved sleep

Neuroprotection Improves cell signalling Anti-inflammatory Normal cell cycle Reduced risk of bone loss and fracture Improved fertility Anti-ageing

Homocysteine and cognitive decline

Prospectively, elevated homocysteine is associated with cognitive decline, white matter damage, brain atrophy, neurofibrillary tangles and dementia, and is a strong modifiable risk factor for vascular dementia and Alzheimer's disease

•77 cross-sectional studies on >34,000 subjects and 33 prospective studies on >12,000 subjects have shown associations between cognitive deficit or dementia and high homocysteine and/ or low B vitamin status (Smith 2008)

•Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective agents against cognitive decline were poorly designed by including subjects unlikely to benefit during the trial period

•In contrast, trials in high-risk subjects, which have taken into account the baseline B-vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer's disease process

Benefits of intervention are most apparent in those individuals with high homocysteine and low B-vitamin status

Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2008 Jun;29(2 Suppl):S143-72. Review. Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016 Jul 17;36:211-39

https://www.ncbi.nlm.nih.gov/pubmed/27431367

Homocysteine and dementia risk factors

• Elevated homocysteine is also associated with cardiovascular disease, diabetes, major depression and cognitive decline

• As levels of homocysteine in the blood are directly influenced by levels of the B-complex vitamins (folate, vitamin B6 and vitamin B12), supplementation with these key nutrients offers preventive strategies for a number of conditions related to high homocysteine

• Studies have shown that supplementing with B6, B12 and folate successfully lowers homocysteine

Clarke R, Harrison G, Richards S; Vital Trial Collaborative Group. Effect of vitamins and aspirin on markers of platelet activation, oxidative stress and homocysteine in people at high risk of dementia. J Intern Med. 2003 Jul;254(1):67-75.

.Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease N Engl J Med. 2006 Apr 13;354(15):1567-77

Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, Linnebank M.Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations.Expert Rev Neurother. 2009 Sep;9(9):1393-412.

ESSENTIAL TO BRAIN STRUCTURE AND MASS

In the transsulfuration pathway, homocysteine can be catabolised to the most important intracellular antioxidant glutathione, with vitamin B6 as a cofactor

In the transmethylation pathway, homocysteine can be transformed to SAMe, with vitamin B12 and folate as cofactors (SAMe is a universal donor of methyl groups, which are used for fatty acid and phospholipid production)

SAME (S-adenosylmethionine)

During high oxidative stress, the one-carbon cycle shifts away from the methylation pathway and production of methyl groups needed for PUFA production, neurotransmitters and DNA methylation, to the transsulfuration pathway, resulting in synthesis of the major intracellular antioxidant glutathione

Assies J, Mocking RJ, Lok A, Ruhé HG, Pouwer F, Schene AH. Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity. Acta Psychiatr Scand. 2014 Sep;130(3):163-80.

The impact of oxidative stress on the one-carbon cycle and long-chain fatty acids

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the aged population

Main pathological features of AD include β-amyloid (Aβ) accumulation and hyper-phosphorylation of the microtubule-associated protein tau, leading to the neuropathological hallmarks of AD, senile plaques and neurofibrillary tangles

Amyloidogenic Aβ peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) involving β- and γ-secretase activity

DHA has been shown to reduce Aβ production in vitro and in animal models of AD

DHA is decreased in post-mortem AD brains, and AD patients have reduced blood DHA levels

DHA has therefore become of major interest for nutritional intervention in AD

Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blümel T, Mylonas NT, Endres K, Grimm HS, Hartmann T. Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. Neurodegener Dis. 2016;16(1-2):44-54.

DHA has numerous biological properties that might be beneficial in AD neurogenesis

It has been previously demonstrated that polyunsaturated fatty acids (PUFAs), especially DHA, are associated with a reduced risk of AD caused by decreased Aβ production

However, in epidemiological studies and dietary interventions, the outcomes of DHA-dependent treatment are controversial

For example the OmegAD study, found no benefits from a 6-month intervention with 1.7g DHA/0.6g EPA in AD patients (n=204)

However, in a subgroup (n = 32) with very mild cognitive dysfunction, a significant (P<.05) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group – although this difference disappeared when adjusted for body weight

“Since our study suggests dose-response relationships between plasma levels of omega-3 FA and preservation of cognition, future omega-3 trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of omega-3 ”

Eriksdotter M, Vedin I, Falahati F, Freund-Levi Y, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Cederholm T, Palmblad J. Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease PatientsDuring Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study. J Alzheimers Dis. 2015;48(3):805-12.

Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease:OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;6 3(10):1402-8.

neurotransmission synaptogenesis neuronal differentiation

synaptic plasticity neurite outgrowth pro-resolvins

(MMSE) Mini-Mental State Examination score

However, DHA is very susceptible to lipid peroxidation and might auto-oxidise and induce lipid peroxidation resulting in oxidative stress, known to be involved in AD pathogenesis

Lipid peroxidation is not only a result of the increased levels of ROS, but also the oxidation products increase the amyloidogenic processing, resulting in a futile cycle

Lipid peroxidation is elevated in human post-mortem AD brains, especially 4-hydroxy-nonenal (HNE) derived from AA

However, oxidised DHA can increase amyloidogenic amyloid precursor protein processing


Burckhardt M, Herke M, Wustmann T, Watzke S, Langer G, Fink A. Omega-3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev. 2016 Apr 11;4:CD009002. doi: 10.1002/14651858.CD009002.pub3. Review.

Non-enzymatic oxidation is caused by ROS attack of PUFAs and produces manifold potentially harmful lipoperoxidation (LPO) products, such as malondialdehyde (MDA; from AA, EPA & DHA), and hydroxynonenals ( HNEs; from AA) and hydroxyhexenals (HHEs; from EPA and DHA)


Even small amounts of oxidised DHA are sufficient to reverse the beneficial effects of DHA, emphasising the importance of preventing DHA from oxidation in nutritional approaches

This might also explain the different results obtained in epidemiological studies dealing with DHA, where small contamination of oxidised DHA could lead to negative/neutral study results

Omega-3 should be combined with appropriate antioxidants in high-risk individuals


4-hydroxynonenal (HNE) is a lipid peroxidation by product, derived from membrane lipid oxidation by ROS

At physiological or low stress levels the major 4-HNE detoxification step is via glutathione; if glutathione levels are compromised 4-HNE accumulates, causing irreversible cell damage

Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signalling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.

Gut microbiota and cognitive behaviour

Caracciolo B, Xu W, Collins S, Fratiglioni L. Cognitive decline, dietary factors and gut-brain interactions. Mech Ageing Dev. 2014 Mar-Apr;136-137:59-69.

Dysbiosis is known to result in low grade inflammation

Recent studies suggest a significant correlation between the changes of gut microbiota and cognitive behaviour:

Neurotransmitters including -aminobutyric acid (GABA), glutamate and serotonin are influenced by gut flora

Disruption of gut microbiota by antibiotic treatment also significantly reduces the level of N-methyl-D-aspartate glutamate receptor (NMDA) in the hippocampus – important for regulating neuronal survival, dendrite & axon development and synaptic plasticity

The development of HPA-axis in germ free mice is abnormal, leading to altered response to stress and reduced expression of brain-derived neurotrophic factor (BDNF)

Cytokines (IL-1, IL-6, TNF-

Acute Phase ProteinsC-reactive protein (CRP), Serum amyloid A (SAA)

PLA2/COX2/LOX

NFκB

Receptor mediated pathways(Toll like receptors [TLR], TNF-, IL-

1)

Inflammation stimulus (i.e. tissue injury, infection, heat

stress, psychological stress)

ProstaglandinsLeukotrienes

ThromboxanesINFLAMMATION

Saturated fatDysbiosis

How do we combat cognitive decline?

At present, healthy diets, antioxidant supplements, the prevention of nutritional deficiencies and moderate physical activity could be considered the first line of defence against the development and progression of pre-dementia and dementia syndromes

Solfrizzi V, Capurso C, D'Introno A, Colacicco AM, Santamato A, Ranieri M, Fiore P, Capurso A, Panza F. Lifestyle-related factors in predementia and dementia syndromes. Expert Rev Neurother. 2008 Jan;8(1):133-58. Review.

The Mediterranean-style diet was first described in the Seven-Country study in the 1950s to 1960s in the south of Europe, where adult life expectancy was among the highest in the world and rates of coronary heart disease, certain cancers and other nutrition-related chronic diseases were among the lowest (Keys et al. 1986)

• The Mediterranean diet may exert its effects on cognitive health through multiple biological mechanisms as relationships with reduced risk of coronary heart disease, hypertension, diabetes, dyslipidaemia and metabolic syndrome have been observed; these conditions have also been associated with mild cognitive impairment, dementia, or Alzheimer’s disease

• Higher adherence to a Mediterranean diet may also facilitate metabolic control because it has been related to improved insulin sensitivity and glucose metabolism

• Higher adherence to a Mediterranean diet helps to dampen oxidative stress – known to increase ‘naturally’ with age and results in oxidative damage - a state often observed in the brain of patients with Alzheimer’s disease

Keys et al., The diet and 15-year death rate in the seven countries study. Am J Epidemiol. 1986 Dec;124(6):903-15.

Lourida I, Soni M, Thompson-Coon J, Purandare N, Lang IA, Ukoumunne OC, Llewellyn DJ. Mediterranean diet, cognitive function, and dementia: a systematic review. Epidemiology. 2013 Jul;24(4):479-89.

Randomised controlled trials to assess the effect on cognition of a nutritional intervention using Mediterranean diet (supplemented with extra-virgin olive oil [EVOO] or mixed nuts) in comparison with a low-fat control diet

2013 - PREDIMED-NAVARRA trial - 6.5 years nutritional intervention - 522 participants at high vascular risk (44.6% men, age 74.6 ± 5.7 years at cognitive evaluation)

Measurements: cognitive performance as a main outcome and cognitive status (normal, mild cognitive impairment [MCI] or dementia) as a secondary outcome. Global cognitive performance was examined by Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT)

2015 -Prevención con Dieta Mediterránea nutrición intervención trial - 6.5 years nutritional intervention 447 participants at high cardiovascular risk (47.9% men, mean age 66.9 years at cognitive evaluation)

Rates of cognitive change over time based on a neuropsychological test battery: Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Animals Semantic Fluency, Digit Span subtest from the Wechsler Adult Intelligence Scale, Verbal Paired Associates from the Wechsler Memory Scale, and the Colour Trail Test

In older populations, compared to a low fat diet, a Mediterranean diet supplemented with olive oil or nuts is associated with improved cognitive function.

Martinez-Lapiscina, E.H.; Clavero, P.; Toledo, E.; Estruch, R.; Salas-Salvado, J.; San Julian, B.S.; Sanchez-Tainta, A.; Ros, E.; Valls-Pedret, C.; Martinez-Gonzalez, M.A. Mediterranean diet improves cognition: The PREDIMED-NAVARRA randomised trial. J. Neurol. Neurosur. Psychiatry 2013, 84, 1318–1325. Valls-Pedret, C.; Sala-Vila, A.; Serra-Mir, M.; Corella, D.; de la Torre, R.; Martínez-González, M.Á.; Martínez-Lapiscina, E.H.; Fitó, M.; Pérez-Heras, A.; Salas-Salvadó, J.; et al. Mediterranean diet and age-related cognitive decline: A randomized clinical trial. JAMA Intern. Med. 2015, 175, 1094–1103.

Olive oil

Fruit

Vegetables

Oily fish

Nuts & seeds

Legumes & cereals

Monounsaturated fat (oleic acid)

Antioxidants (i.e. polyphenols)

Vitamin A,B,C & E

Vitamin D

Omega-3 fatty acids(ALA, EPA & DHA)

Minerals (i.e. selenium, iron &

iodine)

Amino acids (i.e. taurine, tyrosine &

tryptophan)

Moderate red wine

Lean meat

Moderate dairy

Neuronal survivalEnergy metabolismNeurotrophinsNeurotransmissionMembrane fluidityCell membrane integrity Glucose transportNutrient synthesisNutrient metabolismGene expressionMethylationCerebral blood flow

Blood pressureOxidative damageNeuronal cell deathNeuroinflammationFree radicals

Healthy brain

Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.

Fish consumption, cognitive decline and dementia

Brain lipids contain a high proportion of polyunsaturated fatty acids (PUFAs), which are a main component of cell membranes

The physiological roles of omega-3 PUFA in the brain include regulation of cell membrane fluidity, dopaminergic and serotonergic transmission, regulation of cellular signal transduction, brain glucose metabolism, eicosanoid synthesis, gene expression and cell cycle control

High fish consumption tends to be inversely associated with cognitive impairment and decline (Kalmijn 2000)

Elderly people who eat fish or seafood at least once a week are at lower risk of developing dementia, including Alzheimer's disease (Barberger-Gateau et al. 2002)

Meta analysis of 21 studies (181,580 participants) with 4438 cases identified during follow-up periods (2.1-21 y) found increased fish and omega-3 fatty consumption was associated with a statistically significant lower risk of dementia, AD, MCI and PD (Zhang et al. 2016)

Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study.BMJ. 2002 Oct 26;325(7370):932-3.

Kalmijn S. Fatty acid intake and the risk of dementia and cognitive decline: a review of clinical and epidemiological studies. J Nutr Health Aging. 2000;4(4):202-7. Review.

Zhang Y, Chen J, Qiu J, Li Y, Wang J, Jiao J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016 Feb;103(2):330-40.

In 1992, the BNF Task Force on Unsaturated Fatty Acids suggested a desirable population intake for EPA and DHA of 0.5% of energy, which equates to about 8g/week (1.14g/day) for women and 10g/week (1.42g/day) for men, equivalent to 2-3 medium servings of oil-rich fish per week

For a 77kg individual to raise their omega-3 index from 4.2% to 8% they would need a daily dose of 16mg/kg omega-3 (equivalent to 1.25g) (Flock et al. 2013)

Current UK omega-3 recommendations

450mg EPA and DHA daily (2 portions fish weekly, of which one should be oily)

Mean consumption of oily fish (all age groups) was below the recommended one portion (140g) per week (rolling programme for 2012 and 2013 to 2013 and 2014) and equivalent to 13–29 grams per week in children and 54–87 grams per week in adults

Figure source: Stark KD et al. 016

Is omega-3 ‘deficiency’ a global burden?

Higher information processing speed and less impulsivity in those

with a higher Omega-3 Index

Omega-3 increases blood flow to the brain supplying oxygen and fuel delivery, are essential for neurotransmitter production and function, memory, learning, cognition, and brain and neurone cell structure

Benefits restricted to those with sub-optimal omega-3 intake!!

Omega-3 and cognitive decline

• Meta-analysis examined the neuropsychological benefit of omega-3 in randomized RCTs including healthy people, Alzheimer's disease and milder forms of cognitive impairment (e.g. cognitive impairment no dementia [CIND])

• ApoE-ε4 status (genetic risk factor for AD) appears to be a predictor of response to omega-treatment (no protective response)

• Omega-3 fatty acid treatment was associated with a small, but significant, benefit for immediate recall and attention and processing speed in subjects with CIND but not in healthy subjects or those with AD (similar findings from OmegAD study)

“Nevertheless, the present findings suggest that the effects of omega-3 on cognitive decline are not uniform, and that there is a need to identify potentially responsive populations”

Furthermore it is likely that nutrients work synergistically rather than in isolation!

Mazereeuw G, Lanctôt KL, Chau SA, Swardfager W, Herrmann N. Effects of ω-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging. 2012 Jul;33(7):1482.e17-29.

Steps to reducing cognitive decline:

Reduce oxidative damage Increase antioxidant enzymes

Decrease homocysteine levels Manage blood pressure

Modulate inflammation Increase cellular energy

Optimise neuroprotection Enhance neurogenesis

Support cell membrane integrity Optimise neurotransmitter levels

Early intervention is key to successful outcomes

National Diet and Nutrition Survey• Only 8% of 11-18 year olds, 27% of 19-64 year old, and 35% of those ages 65+ are meeting the 5-a-day for fruit

and vegetable consumption

• Mean consumption of oily fish in all age groups remained well below the recommended one portion (140g) per week. Mean consumption was equivalent to 13–29 grams per week in children and 54–87 grams per week in adults

• Key nutrient ‘deficiencies’ (or lower than average intakes) are vitamins A & D and iron. Women and girls appear to be under the recommendations for riboflavin and zinc intake. Many adults appear to be under-consuming magnesium, selenium and potassium

• Actual blood levels of iron, B12 and Vitamin D appear low

• Low iron levels (leading to anaemia) particularly relevant in girls/ women aged 11+ • All age groups are failing to meet the guidelines for fibre intake (18g daily)

• All age groups are exceeding guidelines for both saturated fat and free sugars (used to be known as non-milk extrinsic sugars)

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/551352/NDNS_Y5_6_UK_Main_Text.pdf

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/551352/NDNS_Y5_6_UK_Main_Text.pdf

Non enzymic antioxidants Vitamins A, C, & EPhenolsPolyphenols - flavonoids - isothiocyanates - stilbenes - phenolic acids - lignans - carotenoids - resveratrol

Enzymatic antioxidants require: SeleniumVitamin DCopperManganeseMagnesiumZincAmino acids (i.e. taurine)

Brain proteins, lipids and DNA are vulnerable to

oxidative damage

Prevent, inhibit, repair ROS damage

Metabolism and exogenous damage contribute to the

formation of ROS

Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.

Product recommendations

35

Brain structure & function with antiinflammatory

benefits

Potent antioxidant

Homocysteine control

Supports cognitive

health

Supplement recommendations

Those who habitually consume diets low in omega-3, children with low literacy ability and malnourished and older adults with age-related cognitive decline and mild cognitive impairment seem to benefit most from dietary intervention with omega-3

DHA is for memory and learning if intake is low

EPA in excess of DHA for cognitive performance, in particular attention

Individuals with the lowest base line levels

tend to be the best ‘responders’

‘DHA only’ often resulted in detrimental effects to cognition (increased peroxidation?)

Many benefits of omega-3 are associated

with cardiovascular benefits such as

increased blood flow

>1month intervention needed for benefits to be seen

Benefits of EPA associated with reduced neuroinflammation (lowers IL-1, Il-6 and TNF-a)

EPA restores a healthy

(KYN)/tryptophan ratio

Normal growth and survival of dendritic

neurones

Omega-3 increases BDNF

Omega-3 reduces pro-inflammatory mediators

The presence of neuroinflammation is a common feature of cognitive decline and dementia, with numerous studies linking higher levels of pro-inflammatory products including CRP, IL-6 & TNF- as potential risk factors for cognitive decline

Effects of omega-3 on fasting blood levels of CRP, IL-6 & TNF-•Omega-3 supplementation has a significant lowering effect on all inflammatory markers (sixty-eight RCTs with a total of 4601 subjects)

chronic non-autoimmune diseasesubjects with chronic autoimmune diseasehealthy subjects

Longer duration of supplementation leads to a greater lowering effect (this relationship was greater for EPA than DHA)

Bourassa K, Sbarra DA. Body mass and cognitive decline are indirectly associated via inflammation among aging adults. Brain Behav Immun. 2016 Sep 19.

Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhøj P, Pedersen BK. A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci. 1999 Jul;54(7):M357-64.

Li, K., T. Huang, et al. (2014). "Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor alpha: a meta-analysis." PLoS One 9(2): e88103.

Palta P, Xue QL, Deal JA, Fried LP, Walston JD, Carlson MC. Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women's Health and Aging Study II. J Gerontol A Biol Sci Med Sci. 2015 Jul;70(7):873-8. doi: 10.1093/gerona/glu132. Epub 2014 Aug 26.

Tegeler C, O'Sullivan JL, Bucholtz N, Goldeck D, Pawelec G, Steinhagen-Thiessen E, Demuth I. The inflammatory markers CRP, IL-6, and IL-10 are associated with cognitive function--data from the Berlin Aging Study II. Neurobiol Aging. 2016 Feb;38:112-7.

https://www.ncbi.nlm.nih.gov/pubmed/27658542

Fatty acid absorption

Flooding the body with concentrated high doses of omega-3 can increase inflammation (more so in nutritionally compromised individuals) due to creation of non-enzymatic oxidation end products

Antioxidants can reduce theproduction of unfavourable LPOs

e.g. the high content of astaxanthinin krill oil is possibly due to the presence of unstable free fatty acids

Regular split-dosing with small capsules ismore favourable for delivery of high doses than single large doses

Non-enzymatic oxidation is caused by ROS attack of PUFAs and produces manifold potentially harmful LPOs, such as malondialdehyde (general LPO measure), 8-isoprostane (LPO generated by AA peroxidation), and hydroxynonenals (omega-6 PUFA-derived LPOs) and hydroxyhexenals (omega-3 PUFA-derived LPOs).


Results from intervention trials are ‘cloudy’; it may be that early intervention with omega-3 may be ideal with regard to preventing cognitive decline rather than treating cognitive decline!

Research with EPA or that compares EPA and DHA directly is lacking, especially in the setting of cognitive performance/impairment

It is clear that more experimental data is needed to determine:

The effectiveness of the supplementation in terms of dose, type of -3 PUFA, duration, and the influence of concurrent omega-3 and -6 PUFA in the basal diet The target of omega-3 PUFA action in brain (neurotransmission pathway, inflammation, neurogenesis, etc) The specificity of the impacted cognitive traits (memory, attention, emotivity, stress response, etc) Implicated mechanisms in order to select specific responsive populations (genotype, gender, exposure to stress, etc)

All these parameters constitute confounding factors that seem to greatly influence the results of the numerous reported studies

How to ‘take’ fish oil supplements to minimise peroxidation end products

Smaller capsulesUnlike our competitors, we keep our capsules small, making them not only easier to swallow but to encourage and highlight the importance of split dosing where appropriate

Split-dosingHigh doses (>1g) of omega-3 should be distributed throughout the day. Not only does this help with digestion and uptake of the fatty acids within the oil, but it also ensures that blood levels are sustained throughout the day

Taking the supplements with foodCapsules should never be taken on an empty stomach. Taking EPA/DHA with food (and ideally in the presence of other dietary oil/fat) will increase the body’s natural ability to digest and absorb the fatty acids

Inclusion of vitamin E We add vitamin E to all of our EPA products to protect the free fatty acids from oxidation both pre- and post-digestion

Biomarkers for personalising omega-3 fatty acid dosing

Omega-3 index an early cardiovascular risk indicatorOmega-6 to omega-3 ratio an established marker of long-term health and chronic illnessAA to EPA ratio a measure of ’silent’ or chronic inflammation

A personalised plan aims to achieve:an omega-3 index of more than 8% an omega-6 to omega-3 ratio of between 3 and 4an AA to EPA ratio of between 1.5 and 3

Free radical damage and

oxidative stressSkin

LungsInflammation

Cardiovascular

BrainImmunity

Ageing

Ubiquinol deficiency alters mitochondria function and lowers antioxidant status, leading to increased free radical generation

A free radical has an electron missing from its outer shell

X

Ubiquinol donates anelectron to a free radical

X

Ubiquinol donates electrons to other

antioxidants

‘Recharged’ antioxidants (i.e. vitamins C & E, lipoic acid) can

donate electrons to free radical

Ubiquinol – the antioxidant/antioxidant recycler

Time (hours)

VESIsorb®

Therapeutic level

120mg single dose of VESIsorb® delivered CoQ10 reaches therapeutic levels within 2 hours, reaching maximum blood plasma levels (6.89 g/mL) (Cmax) within around 4 hours (Tmax)

In contrast, 120mg single dose of oil-based CoQ10 reaches maximum blood plasma levels (2.44 g/mL) within 5 hours and fails to achieve therapeutic levels

VESIsorb® increases the bioavailability of CoQ10 by 622%

Oil-based

Cmax

Tmax

VESIsorb® delivered CoQ10 is absorbed FASTER, reaching concentrations that are STRONGER and stays in the body LONGER than generic delivery methods

Managing homocysteineHighly bioavailable (‘body-ready’) micronutrient activesFormulated at proven dosages for enhanced efficacyStrong benefits supported by strong health claimsOffers benefits for cardiovascular health, brain function and mood balanceSynergistic benefits alongside the Igennus clinical omega-3 range Small, easy-to-swallow tablets optimised for split-dosingSplit-dosing overcomes bioavailability issues related to vitamin B12 intake and maintains optimal blood levels of key B-vitaminsSuitable for vegetarians & vegans Suitable for adults and children aged 7+

Ingredient featuresFolate ([6S]-5-methyltetrahydrofolate) vs folic acid Quatrefolic® provides the metabolic reduced folate form utilised and stored in the human body, as (6S)-5-methyltetrahydrofolate, and may benefit certain genetic defects that influence folate metabolism.Quatrefolic® overcomes accumulation of unmetabolised folic acid (UMFA) arising from standard folic acid supplementation, which has no biological function and whose effects are not yet known.

Vitamin B2 (riboflavin-5-phosphate) As with many B-vitamins, riboflavin must be converted to its active form – riboflavin-5-phosphate – in order for it to be utilised by the body.

As absorption of riboflavin occurs in the upper gastrointestinal tract, a compromised digestive system can adversely affect the body's ability to convert riboflavin to riboflavin-5-phosphate.

Vitamin B6 (pyridoxal-5-phosphate)Vitamin B6 exists in 6 forms but only the pyridoxal-5-phosphate form has cofactor activity.

Several inborn errors of B6 metabolism exist, which can compromise vitamin B metabolism to pyridoxal-5-phosphate.

Pyridoxal-5-phosphate is required for approximately 100 enzymes that are important in the metabolism of neurotransmitters and other neuroprotective compounds.

Sweeney MR, Staines A, Daly L, Traynor A, Daly S, Bailey SW, Alverson PB, Ayling JE, Scott JM: Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification? BMC public health 2009, 9:295. Surtees et al. “Inborn errors affecting vitamin B6 metabolism” Future Neurol 2006, 5:615Powers HJ: Riboflavin (vitamin B-2) and health. The American journal of clinical nutrition 2003, 77:1352-1360.

49

A simple, expertly formulated, 1-a-day dual capsule system

Ultra concentrated MindCare® omega-3 EPA & DHA capsules with vitamins D & EPrecisely formulated to target and support

brain function (250mg DHA plus 410 mg EPA

per capsule) using the body-ready rTG form of

omega-3 that is nature-identical and easily

absorbed by the body

MindCare® micronutrient capsules contain:full B complex plus zinc, selenium, vitamin C and targeted ACTIVES Target distinct areas of brain health with a

comprehensive blend of synergistic vitamins,

minerals and specialist actives at proven,

effective levels and in super-bioavailable forms

MindCare® is based on cutting-edge nutrition science and combines premium triglyceride omega-3 fish oil containing 80% active doses of EPA and DHA with scientifically proven nutrients for various aspects of brain health

MindCare® BALANCE Magnesium glycinate and L-Theanine with their natural

calming effects act as relaxants, reduce feelings of stress and

reduce anxiety

MindCare® FOCUSAcetyl-L-Carnitine, L-Theanine, taurine and caffeine heighten mental alertness and support concentration, memory and

focus

MindCare® LIFT Magnesium glycinate and 5-HTP

help to regulate neurotransmitters required for

mood balance

MindCare® PROTECT N-Acetyl L-Cysteine, alpha-lipoic

acid and resveratrol help protect against

neuroinflammation and improve and support energy

metabolism in the brain

Highly bioavailable micronutrients (vitamins C , D3 & E; vitamins B1, B2, B3, B5, B6, B7, B12 & folate; minerals zinc & selenium) support immune & detoxification enzyme-mediated pathways. They support homocysteine recycling required for the production of

neurotransmitters, enhance neurotransmission via regulation of receptors, transporters and ion channels, support natural stress response pathways, ensure optimal delivery of fuel to the brain, enhance cognition, relaxation, sleep, mental focus and reduce stress

and oxidative stress

Ultra concentrated MindCare® omega-3 EPA & DHA capsulesupports cognitive function, mental performance

MindCare® micronutrient capsules

Supporting antioxidant defences

Alpha lipoic acid is an endogenous antioxidant and essential cofactor for many enzyme complexes that interrupt cellular oxidative processes

Increases acetylcholine production by activation of choline acetyl-transferase Increases glucose uptake Acts as a metal chelator Down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF-a and inducible nitric oxide synthase Scavenges lipid peroxidation products such as 4-hydroxynonenal (HNE) and acrolein

Vitamin EAntioxidant protection

Vitamin C Further supports detoxification, provides antioxidant protection against free radicals Reduces tiredness and fatigueNecessary for the proper functioning of the CNS and psychological functioning

(lui, 2007; Moreira et al., 2007; Maczurek et al., 2008; Salinthone et al., 2008)

Vascular processes Calcium homeostasis

Oxidative stress

A and Tau accumulation

Inflammation and immune system

Neurotransmission

Proposed mechanisms of vitamin D-mediated multi-targeted effects in cognitive decline

Landel V, Annweiler C, Millet P, Morello M, Féron F. Vitamin D, Cognition and Alzheimer's Disease: The Therapeutic Benefit is in the D-Tails. J Alzheimers Dis. 2016 May 11;53(2):419-44.

Magnesium

• Regulates the CNS via – neurotransmitter synthesis– neurone activity – synaptic plasticity

• Vitamin B6 absorption• Required by 325 enzymes

(many of which act in the brain)• Neurone health, synaptic plasticity, learning and memory

Low magnesium levels linked to anxiety, depression, irritability, insomnia, confusion….

Magnesium as glycinate provides a bioavailable and effective magnesium source

Glycine promotes healthy immune, digestive and central nervous systems, production of human growth hormones and creatine

Zinc •Essential to the production of neurotransmitters•Enhances neurotransmission via interaction with receptors, transporters and ion channels in the neurone and synapse•Low zinc status is linked to cognitive impairment via epigenetic changes of the brain-derived neurotrophic factor (BDNF) gene

Selenium•Up-regulates glutathione production•Main component of antioxidant enzymes•Supports proper adrenal function – commonly disrupted by high stress and poor diet – leads to poor sleep, memory problems and fatigue • Low selenium status is a risk factor for cognitive decline!Berr C, Arnaud J, Akbaraly TN. Selenium and cognitive impairment: a brief-review based on results from the EVA study. Biofactors. 2012 Mar-Apr;38(2):139-44.

Hu YD, Pang W, He CC, Lu H, Liu W, Wang ZY, Liu YQ, Huang CY, Jiang YG. The cognitive impairment induced by zinc deficiency in rats aged 0 2 months related to BDNF DNA methylation changes in the ∼hippocampus. Nutr Neurosci. 2016 Jun 22:1-7.

Each capsule provides 410 mg EPA, 250 mg DHA and 1000 iu vitamin D3 for intensive daily support. The omega-3 is provided in the superior rTG form, which is body-ready and delivers higher levels of omega-3 into cells faster than standard fish oil and krill oil.

This ultra-pure supplement is sourced from wild, sustainable anchovies and the oil is purified to remove all trace of mercury, dioxins and PCBs. Natural lemon oil prevents fish reflux.

SUPER CONCENTRATED

OMEGA-3WILD FISH OIL & VITAMIN D3

ADVANCED

MULTIVITAMIN & MINERALS

Pure Essentials Advanced Multivitamin & Minerals is a comprehensive multi-nutrient supplement, featuring full spectrum body-ready methylated B-vitamins and active mineral forms. Enhanced with a slow-release delivery system, this supplement steadily releases nutrients for optimal absorption and uptake into the bloodstream. This advanced formula is the ideal all-round multivitamin & mineral supplement to support optimal wellbeing.

Education Technical

Sophie TullyNutrition Education Manager

[email protected]

Dr Nina Bailey Head of Nutrition

[email protected] @DrNinaBailey

mailto:[email protected]

nutritional strategies for cognitive decline

Health & Medicine